Cysteamine-induced adrenocortical necrosis in rats

McComb, Donna J.; Kovacs, K; Horner, Heidi C.; Gallagher, George; Schwedes, U.; Usadel, K. H.; Szabó, Sándor

doi:10.1016/0014-4800(81)90025-3

Cited by 28 publications

(11 citation statements)

References 24 publications

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“…Namely, among the most potent duodenal ulcerogens, cysteamine and cystamine do produce adrenal damage; propionitrile and n-butyronitrile are virtually devoid of this action (7)(8)(9)(10)(11). These data also suggested, like the present analysis, that sulfhydryl and double bonds enhance the adrenocorticolytic action of chemicals (10,12,13).…”

Section: Implications For Pathogenesis Of Organ Lesions and Drug Designsupporting

confidence: 89%

“…Indeed, preliminary toxicologic studies indicated no strong correlation between the potency of the chemicals to induce duodenal ulcer and adrenal necrosis in rats (1,10,13). Namely, among the most potent duodenal ulcerogens, cysteamine and cystamine do produce adrenal damage; propionitrile and n-butyronitrile are virtually devoid of this action (7)(8)(9)(10)(11).…”

Section: Implications For Pathogenesis Of Organ Lesions and Drug Designmentioning

confidence: 99%

“…Acrylonitrile, for example, is a weak duodenal ulcerogen but a very potent adrenocorticolytic chemical (12). Propionitrile exerts the opposite effects, while cysteamine is very potent in producing both duodenal ulcer and adrenal necrosis in the rat (6,10,13). Nevertheless, acrylonitrile and cysteamine may also serve as animal models of human adrenocortical insufficiency or hemorrhagic adrenocortical necrosis, otherwise known as adrenal apoplexy or Waterhouse-Friderichsen syndrome (12,13).…”

mentioning

confidence: 99%

“…Propionitrile exerts the opposite effects, while cysteamine is very potent in producing both duodenal ulcer and adrenal necrosis in the rat (6,10,13). Nevertheless, acrylonitrile and cysteamine may also serve as animal models of human adrenocortical insufficiency or hemorrhagic adrenocortical necrosis, otherwise known as adrenal apoplexy or Waterhouse-Friderichsen syndrome (12,13). Structure-activity studies with derivatives of propionitrile and cysteamine thus revealed not only appropriate animal models of duodenal ulcer and adrenal necrosis but also demonstrated that these lesions can be induced in experimental animals in a rational and predictable fashion (10,11).…”

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confidence: 99%

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Predicting chemically induced duodenal ulcer and adrenal necrosis with classification trees.

Giampaolo¹,

Gray²,

Olshen³

et al. 1991

Proc. Natl. Acad. Sci. U.S.A.

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Binary tree-structured statistical classification algorithms and properties of 56 model alkyl nucleophiles were brought to bear on two problems of experimental pharmacology and toxicology. Each rat of a learning sample of 745 was administered one compound and autopsied to determine the presence of duodenal ulcer or adrenal hemorrhagic necrosis. The cited statistical classification schemes were then applied to these outcomes and 67 features of the compounds to ascertain those characteristics that are associated with biologic activity. For predicting duodenal ulceration, dipole moment, melting point, and solubility in octanol are particularly important, while for predicting adrenal necrosis, important features include the number of sulfhydryl groups and double bonds. These methods may constitute inexpensive but powerful ways to screen untested compounds for possible organ-specific toxicity. Mechanisms for the etiology and pathogenesis of the duodenal and adrenal lesions are suggested, as are additional avenues for drug design.Duodenal ulcer disease is a frequent and poorly understood disorder. Quantitative structure-activity studies of chemical duodenal ulcerogens are of great interest, since they can yield toxicologic information regarding the etiology and mechanisms of ulceration, suggest pharmacologic approaches, and ultimately bear upon clinical practice. Duodenal ulcers are 2-4 times more frequent than gastric ulcers in humans, yet much more is known about the pathophysiology of gastric mucosal lesions than about duodenal ulceration (1). This is due in part to the lack of availability of requisite animal models of duodenal ulcer disease.It has long been known that gastric ulcers and erosions can be induced easily in both humans and laboratory animals by a variety of chemicals (in toxic doses) that elicit stress response. Selye (2) was the first to recognize that during stress a common set of pathogenetic mechanisms link many of the different etiologic factors. Until recently, animal models of duodenal ulcers were scarce (1). Available methods, such as pantothenic acid deficiency in certain strains of rats, the prolonged infusion of secretagogues, or the local application of acetic acid on the duodenum, were cumbersome and typically produced a low yield of duodenal ulcers (1, 3, 4). The first rapidly developing experimental duodenal ulcer was produced by subcutaneous administration of propionitrile, which consistently induced solitary, and often perforating, duodenal ulcers in 80%o of rats (5). Subsequently, cysteamine was also found to produce duodenal ulcers in rats (6). This model offered advantages since the ulcers developed more rapidly and consistently than after propionitrile administration, and only one to three doses were required. Since then, several other compounds have been shown to be duodenal ulcerogens, including 3,4-toluenediamine (7), 3,4-toluenedithiol, and n-butyronitrile (8, 9). The latter two chemicals were discovered during our initial structure-activity studies, which revealed th...

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Section: Implications For Pathogenesis Of Organ Lesions and Drug Designsupporting

confidence: 89%

Section: Implications For Pathogenesis Of Organ Lesions and Drug Designmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Predicting chemically induced duodenal ulcer and adrenal necrosis with classification trees.

Giampaolo¹,

Gray²,

Olshen³

et al. 1991

Proc. Natl. Acad. Sci. U.S.A.

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“…In the adrenal glands of normal rats, fragments of chromaffin cell were mostly in found in sinusoidal medullary tissue and occasionally in the capillaries of zona reticularis (5,18,29). In the rats treated with cysteamine, acrynitrile, and tyrazole, a large quantity of chromaffin-cell fragments and platelets were detected in the capillaries of zona fasciculata and reticularis as early as 30 min after the treatment (21,28,29). The increase in concentration of catecholamines, especially dopamine, though transient, confirmed the ultrastructural observation.…”

Section: Discussionmentioning

confidence: 99%

Prompt Recovery of Damaged Adrenal Medullae Induced by Salinomycin

Chen-Pan

Pan

Yamamoto³

et al. 1999

Toxicol Pathol

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The morphologic changes in the adrenal medullae of rats treated with an ionophore antibiotic, salinomycin, are described. Male rats of approximately 7 wk of age were treated orally with a single dose of salinomycin at 80 mg/kg body weight. Following this treatment, the adrenal glands were examined, using immunohistochemistry, for neurofilament, laminin, fibronectin, and S-100 protein; the glands were also examined using transmission electron microscopy. One hour after the treatment, a karyopyknosis was observed in the clusters of affected chromaffin cells in which the neurofilament, laminin, and fibronectin were present. The lesions became progressively conspicuous between hours 5 and 10. Ultimately, the outcome was cell lysis. Five hours after salinomycin treatment, unaffected chromaffin cells strongly stained to tyrosine hydroxylase. At 10 hr, new chromaffin cells, which were irregular in shape with electron-dense cytoplasm (dark cell), that were strongly stained for tyrosine hydroxylase appeared at the basement membrane site of the necrotic clusters, and these cells contained very few immature catecholamine granules of less than 80 nm. At 17 hr, the catecholamine granules increased in number and size to about 200 nm. The newly formed chromaffin cells grew within the clusters to fill in the medulla by 24 hr, and cytoplasmic granules progressively increased in number and size. The interstitial tissue was seen to be edematous at 5 hr. New capillaries were found in the adrenal medullae of both control and salinomycin-treated rats. The protruding chromaffin cells (protruding cells), which we previously described in normal rats, were also observed in salinomycin-treated rats, which suggests that holocrine secretion is performed in the adrenal medullae. The results indicated that the rat adrenal medullae have the ability to make a rapid recovery after an insult by salinomycin.

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Subacute and chronic action of acrylonitrile on adrenals and gastrointestinal tract: Biochemical, functional and ultrastructural studies in the rat

Szabó

Gallagher

Silver

et al. 1984

J of Applied Toxicology

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A single dose of acrylonitrile can produce fatal adrenal apoplexy within approximately 2 h. Our previous studies also indicate that multiple injections of the chemical cause acute hemorrhagic and occasional nonperforating duodenal ulcers. Other authors have reported increase in gut and lung neoplasia after chronic exposure. The present study was designed to elucidate the subacute and chronic actions of acrylonitrile on the adrenals, stomach and duodenum by correlating biochemical, functional and morphologic investigations, as well as to gain insight into the mechanisms of action of acrylonitrile. Rats were exposed to 0, 0.0001% (1 ppm), 0.002%, 0.01%, 0.05% or 0.2% acrylonitrile in drinking water, or to the same amount of the chemical given through daily gavage, for 7, 21 or 60 days. Acrylonitrile caused a time- and dose-dependent decrease in plasma corticosterone levels; aldosterone was affected only by the 'high' dose and prolonged time of exposure. Young rats were more susceptible than adults to this action of acrylonitrile. The adrenal cortex, especially the zona fasciculata, was atrophic in rats that had ingested the nitrile through drinking water. At 0.05% and 0.2%, it also caused decreased food intake and body weight gain. The adrenals were enlarged with a hyperplastic zona fasciculata after daily doses of a bolus of acrylonitrile. Ingestion of the chemical did not interfere with compensatory enlargement of the adrenal gland following unilateral adrenalectomy. On the other hand, the ACTH-induced elevation of corticosterone plasma concentration was significantly attenuated by acrylonitrile in drinking water. Electron microscopy of the adrenal glands revealed no consistent changes in the steroid-producing cells. We thus postulate that accelerated turnover of circulating corticoids and/or interference with the secretion or action of ACTH may primarily be responsible for the decreased plasma levels of corticosterone and aldosterone in rats that ingest acrylonitrile. The mucosa in the stomach at the junction of the forestomach and glandular region of animals that had ingested acrylonitrile was hyperplastic. The corpus also showed regional mucosal hyperplasia with the appearance of 'cobble-stoning'. These changes were preceded and associated with an elevated concentration of non-protein sulfhydryls mostly in the mucosa of the glandular stomach. A similar, less prominent elevation also occurred in the proximal duodenum. These alterations may resemble the preneoplastic combination of elevated glutathione and focal hyperplasia described in the liver with hepatocarcinogens.(ABSTRACT TRUNCATED AT 400 WORDS)

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Cysteamine-induced adrenocortical necrosis in rats

Cited by 28 publications

References 24 publications

Predicting chemically induced duodenal ulcer and adrenal necrosis with classification trees.

Predicting chemically induced duodenal ulcer and adrenal necrosis with classification trees.

Prompt Recovery of Damaged Adrenal Medullae Induced by Salinomycin

Subacute and chronic action of acrylonitrile on adrenals and gastrointestinal tract: Biochemical, functional and ultrastructural studies in the rat

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